Dr. Ambati plans to continue his research into disrupting pathways of new blood vessel formation within cells;this will augment and possibly transcend the current therapies of blockade outside the cell. By using novel techniques to disrupt the gene messaging systems which communicate directions to form new blood vessels, this proposal has the potential of advancing therapies for a variety of blinding conditions, including injury to the cornea (the front part of the eye), diabetes damage to the retina, and macular degeneration. This could translate into improved outcomes for veterans who sustain eye injury and require corneal transplantation (as fighting blood vessel formation is essential to corneal transparency and preventing corneal transplant rejection), as well as improved vision for veterans with diabetic retinopathy and macular degeneration, which are the leading cause of blindness among older veterans. Further, this approach of fighting blood vessel formation by targeting key genetic events within the cell could have major beneficial applications to cancer. PUBLIC HEALTH RELEVANCE: Relevance to Veterans'Health: Corneal neovascularization is a sight-threatening complication of ocular injury, from shrapnel, improvised explosive devices (IEDs), or blowing sand. Regression of corneal neovascularization will hopefully facilitate vision restoration in soldiers or veterans who sustained combat eye injuries. Of the more than 1 million veterans with low vision (defined as less than 20/70), about half are due to macular degeneration or diabetes. The VA spends >$43,000 per low vision case for rehabilitation [59] and >$30,000 per year per patient on LucentisTM therapy, the only approved treatment in the VA for neovascular AMD. This proposal's novel approaches to inhibiting VEGF intracellularly may hopefully translate into better treatment of corneal injury and macular degeneration. It may eventually be of relevance in helping treatment of cancer &diabetic retinopathy.